Background: AZD1775 (formerly MK-1775) is a potent and selective inhibitor of Wee1, a kinase that phosphorylates CDC2. Phosphorylation of CDC2 inactivates the CDC2/cyclin B complex and is therefore essential for normal G2 checkpoint function. As most p53-deficient tumors lack a functional G1 checkpoint, they rely on the G2 checkpoint for cell cycle arrest in response to DNA damage. G2 checkpoint abrogation, using a Wee1 inhibitor may therefore sensitize p53 deficient tumor cells to DNA-damaging anti-cancer agents. In a phase I study the maximum tolerated dose (MTD) of AZD1775 in combination with carboplatin demonstrated target engagement (NCT00648648). Methods: Patients (pts) with p53 mutated ovarian cancer refractory or resistant ( < 3 months) to standard first line therapy (carboplatin plus paclitaxel) were re-exposed to carboplatin (AUC 5), plus 5 bi-daily doses of 225 mg AZD1775 in a 21 day cycle (MTD) (NCT01164995). p53 mutation status was analyzed by both sequencing analysis (TP53 exons 2-10) and AmpliChip TP53 array (TP53 exons 2-11). Response evaluation was performed according to RECIST 1.0, volumetric tumor measurement (enhanced RECIST) and CA-125 blood levels. Results: Bone marrow toxicity, fatigue, diarrhea, nausea and vomiting were the most common adverse events. Out of 24 pts enrolled, 22 pts were evaluable for study endpoints. As best response (RECIST 1.0), 6 pts (27%) showed confirmed partial response (PR) with a median progression-free survival (PFS) of 10.9 months. Nine pts (41%) had stable disease and 7 pts (32%) had progressive disease as best response, with a median PFS of 5.3 and 1.3 months, respectively. Conclusions: AZD1775 is a first in class Wee1 inhibitor that in combination with carboplatin is well tolerated and shows promising anti-tumor activity in p53 mutated ovarian cancer refractory or resistant ( < 3 months) to standard first line therapy. Clinical trial information: NCT01164995